From Cochlear Cell Death Pathways To New Pharmacological Therapies

Abstract

Ototoxic drugs, intense sound or age-related hearing loss recruit most of the apoptotic pathways, but also several additional enzymatic pathways which eventually result in cell death. Here, we discuss therapeutic strategies based on the inhibition of regulators or executors of apoptotic cell death pathways and on the use of antioxidants.

Specific synaptopathies diversify brain responses and hearing disorders: you lose the gain from early life

“…These low-SR auditory fibers are apparently also preferentially lost with age (Sergeyenko et al 2013 ) and may explain the finding that aging people experience increasing difficulties of hearing in noise well before any loss of hair cells (Bharadwaj et al 2014 ; Dubno et al 1984 ; Makary et al 2011 ). The loss of low-SR fibers is currently linked to glutamate excitotoxicity after noise and the lower degree of clearance of released glutamate close to these fibers (for reviews, see Moser et al 2013 ; Wang and Puel 2008 ). This reduced degree of clearance of released glutamate is linked to a difference in proteins involved in the clearance of glutamate, such as the glutamate-aspartate transporter (GLAST), which has been found to be less strong on the modiolar side of IHCs, where most low-SR fibers make contacts (Furness and Lawton 2003 ).…”

“…Type II terminals also do not express the same AMPA type glutamate receptors (e.g., GluA2) as do the type I terminals (Liberman et al 2011 ). Therefore, glutamate excitotoxicity is currently assumed to be a pathology restricted to the IHC area and not to the OHC area (for reviews, see Bharadwaj et al 2014 ; Moser et al 2013 ; Wang and Puel 2008 ). What also appears to be certain is that, gradually over time and secondary to the degeneration of the afferent dendrites of AN fibers, spiral ganglion cells undergo neurodegeneration, as shown after glutamate-induced excitotoxic trauma in vitro (Puel et al 2002 ; Wang and Green 2011 ) and in vivo after intense tone exposure (Godfrey et al 2012 ) or after long-term mild trauma (Lin et al 2011 ).…”

Molecular and Cellular Mechanisms of Loss of Residual Hearing after Cochlear Implantation

“…61 In cochlear implantation, one would therefore expect cortico steroids to act by reducing the inflammatory response and thus protecting the sensory cells from necrotic or apoptotic death. Apoptosis can be triggered by the activation of numerous pathways involving cytochrome C release, NF-κB activation, PI3K (phosphatidyl inositol 3 kinase) and Akt1 (protein kinase B1) activation, or MAPK (mitogen activated protein kinase) and JNK activation 62,63 (Fig 1). It has been shown in vitro that dexamethasone prevents TNFα-induced apoptosis through the activation of NF-κB and PI3K/Akt signaling.…”

Toward Cochlear Therapies

“…JNK also plays an important role in the extrinsic and intrinsic apoptotic pathways (86). In the cochlea, it can be activated by various forms of insult, such as loss of neurotrophic support, drug ototoxicity, and intense sound exposure (455). A predominant nuclear JNK substrate is c-Jun, a transcription factor of the activator protein 1 complex (69).…”

“…Aminoglycoside-induced cochlear cell damage occurs mainly through an apoptotic process due to the generation of ROS. The ROS activate various pathways including the E2F1-cyclin dependent kinase 1 (CDK1) pathway, MAPK-JNK, NF-B, and Fas-Fas ligand signaling pathways, resulting in intrinsic and extrinsic apoptotic cell death (21,61,455). Similar to aminoglycosides, CDDP induces DNA damage and free radical production in the cochlea and triggers the activation of intrinsic and extrinsic, caspase-dependent and also caspaseindependent apoptotic pathways (30,455).…”